Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals

Andranik Ivanov; Sebastian Memczak; Emanuel Wyler; Francesca Torti; Hagit T. Porath; Marta R. Orejuela; Michael Piechotta; Erez Y. Levanon; Markus Landthaler; Christoph Dieterich; Nikolaus Rajewsky

doi:10.1016/j.celrep.2014.12.019

Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals

Andranik Ivanov, Sebastian Memczak, Emanuel Wyler, Francesca Torti, Hagit T. Porath, Marta R. Orejuela, Michael Piechotta, Erez Y. Levanon, Markus Landthaler, Christoph Dieterich, Nikolaus Rajewsky

The Mina and Everard Goodman Faculty of Life Sciences - at Bar-Ilan University

Research output: Contribution to journal › Article › peer-review

885 Scopus citations

Abstract

Circular RNAs (circRNAs) are a large class of animal RNAs. To investigate possible circRNA functions, itis important to understand circRNA biogenesis. Besides human ALU repeats, sequence features that promote exon circularization are largely unknown. We experimentally identified circRNAs in C.elegans. Reverse complementary sequences between introns bracketing circRNAs were significantly enriched in comparison to linear controls. By scoring the presence of reverse complementary sequences in human introns, we predicted and experimentally validated circRNAs. We show that introns bracketing circRNAs are highly enriched in RNA editing or hyperediting events. Knockdown of the double-strand RNA-editing enzyme ADAR1 significantly and specifically upregulated circRNA expression. Together, our data support a model of animal circRNA biogenesis in which competing RNA-RNA interactions of introns form larger structures that promote circularization ofembedded exons, whereas ADAR1 antagonizes circRNA expression by melting stems within these interactions.

Original language	English
Pages (from-to)	170-177
Number of pages	8
Journal	Cell Reports
Volume	10
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2014.12.019
State	Published - 13 Jan 2015

Bibliographical note

Publisher Copyright:
© 2015 The Authors.

Funding

A.I. and N.R. thank Sebastian Kadener (Hebrew University), Albrecht Bindereif (University of Giessen), and Marvin Jens (N.R. lab) for helpful discussions. We thank all members of the N.R. lab for discussions and support. This work was supported by German-Israeli-Foundation for Scientific Research and Development (G.I.F) and German Ministry for Education and Research (SatNet program).

Funders	Funder number
German-Israeli Foundation for Scientific Research and Development
Bundesministerium für Bildung und Forschung

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10.1016/j.celrep.2014.12.019

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title = "Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals",

abstract = "Circular RNAs (circRNAs) are a large class of animal RNAs. To investigate possible circRNA functions, itis important to understand circRNA biogenesis. Besides human ALU repeats, sequence features that promote exon circularization are largely unknown. We experimentally identified circRNAs in C.elegans. Reverse complementary sequences between introns bracketing circRNAs were significantly enriched in comparison to linear controls. By scoring the presence of reverse complementary sequences in human introns, we predicted and experimentally validated circRNAs. We show that introns bracketing circRNAs are highly enriched in RNA editing or hyperediting events. Knockdown of the double-strand RNA-editing enzyme ADAR1 significantly and specifically upregulated circRNA expression. Together, our data support a model of animal circRNA biogenesis in which competing RNA-RNA interactions of introns form larger structures that promote circularization ofembedded exons, whereas ADAR1 antagonizes circRNA expression by melting stems within these interactions.",

author = "Andranik Ivanov and Sebastian Memczak and Emanuel Wyler and Francesca Torti and Porath, {Hagit T.} and Orejuela, {Marta R.} and Michael Piechotta and Levanon, {Erez Y.} and Markus Landthaler and Christoph Dieterich and Nikolaus Rajewsky",

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year = "2015",

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doi = "10.1016/j.celrep.2014.12.019",

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AU - Ivanov, Andranik

AU - Memczak, Sebastian

AU - Wyler, Emanuel

AU - Torti, Francesca

AU - Porath, Hagit T.

AU - Orejuela, Marta R.

AU - Piechotta, Michael

AU - Levanon, Erez Y.

AU - Landthaler, Markus

AU - Dieterich, Christoph

AU - Rajewsky, Nikolaus

PY - 2015/1/13

Y1 - 2015/1/13

N2 - Circular RNAs (circRNAs) are a large class of animal RNAs. To investigate possible circRNA functions, itis important to understand circRNA biogenesis. Besides human ALU repeats, sequence features that promote exon circularization are largely unknown. We experimentally identified circRNAs in C.elegans. Reverse complementary sequences between introns bracketing circRNAs were significantly enriched in comparison to linear controls. By scoring the presence of reverse complementary sequences in human introns, we predicted and experimentally validated circRNAs. We show that introns bracketing circRNAs are highly enriched in RNA editing or hyperediting events. Knockdown of the double-strand RNA-editing enzyme ADAR1 significantly and specifically upregulated circRNA expression. Together, our data support a model of animal circRNA biogenesis in which competing RNA-RNA interactions of introns form larger structures that promote circularization ofembedded exons, whereas ADAR1 antagonizes circRNA expression by melting stems within these interactions.

AB - Circular RNAs (circRNAs) are a large class of animal RNAs. To investigate possible circRNA functions, itis important to understand circRNA biogenesis. Besides human ALU repeats, sequence features that promote exon circularization are largely unknown. We experimentally identified circRNAs in C.elegans. Reverse complementary sequences between introns bracketing circRNAs were significantly enriched in comparison to linear controls. By scoring the presence of reverse complementary sequences in human introns, we predicted and experimentally validated circRNAs. We show that introns bracketing circRNAs are highly enriched in RNA editing or hyperediting events. Knockdown of the double-strand RNA-editing enzyme ADAR1 significantly and specifically upregulated circRNA expression. Together, our data support a model of animal circRNA biogenesis in which competing RNA-RNA interactions of introns form larger structures that promote circularization ofembedded exons, whereas ADAR1 antagonizes circRNA expression by melting stems within these interactions.

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Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals

Abstract

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